This is a renewal application for the NIDA sponsored K02 Independent Scientist Award. The candidate is a tenured Associate Professor in the Department of Neuroscience at the Scripps Research Institute - Florida. The long term goal of the candidate is to elucidate the mechanisms of G protein signaling regulation in the basal ganglia as a necessary prerequisite to understanding neurological diseases and addiction and developing means of their treatment. Proposed studies during the next period will focus on delineating the mechanisms by which key striatal RGS proteins: RGS9-2 and RGS7 regulate cellular signaling. Our recent findings indicate that the function of the two RGS proteins is closely intertwined. They exist as macromolecular complexes with several binding partners and undergo striking remodeling upon drug exposure as well as changes in neuronal excitability suggesting that plasticity in the RGS system contributes to molecular adaptations leading to addiction. Specifically, the research will seek to (1) to establish how interplay between RGS complex components contribute to behavioral response to opioids and cocaine, (2) delineate molecular specificity of RGS action in G protein pathways and (3) understand the mechanisms behind the integration of RGS complexes with the adenylyl cyclase signaling, the key second messenger system implicated in addiction. The strategy proposed to address these Aims will entail a synergistic combination of genetic, behavioral, biochemical, and physiological approaches, exploiting the existence of a powerful array of reagents and animal models. In addition to the scientific directions, the applicant will focus on career development activities tht will include training in emerging approaches and techniques through close interactions with a team of collaborating investigators, participation in community outreach events, building a center of excellence in drug addiction research and active engagement in activities pertaining to issues in responsible conduct of research. The K02 award will play an essential role in advancing Dr. Martemyanov's career by allowing continued focus on drug addiction research and protecting the candidate from excessive teaching and administration.